Follicular development involves important morphological and functional changes in thecal and granulosa cells (proliferation, steroidogenesis, gonadotropin sensitivity) as well as in the oocyte (cytoplasmic and nuclear maturation). There is substantial evidence that gonadotropins play a key role in controlling folliculogenesis. However, other factors (steroids, growth factors) of endocrine and paracrine origin also appear to act in concert with the gonadotropins to control follicular development. Activins and inhibins, members of the transforming growth factor-beta family, and their binding protein, follistatin, have local functions in regulation of follicular development. The exact mechanism by which dominant follicles are selected to develop to preovulatory status in preference to other more or less mature follicles remains to be elucidated. The overall goal of this proposal is to determine the intrafollicular milieu of activins, inhibins, follistains and activin receptors in developing and regressing follicles during the onset of puberty and reproductive cyclicity and determine how the relative proportions of these regulators are deterministic of follicular function. Sheep will be used as the animal model. Experiments in the current proposal will address the unifying hypothesis that intrafollicular abundance of activins, relative to inhibins and follistatin, is important in determining which follicles within a cohort of follicles undergo atresia and which follicles escape atresia and become dominant, estrogenic follicles. Furthermore, the relative abundance of follicular activins, compared to inhibins and follistatin, is greater in healthy, developing follicles than in atretic follicles. Specific Aims of the proposal follow: Specific Aim 1: To characterize changes in intra-follicular activins, inhibins, follistatin and activin receptors during-pubertal onset and determine the roles of FSH and LH in mediating these changes. Specific Aim 2: To characterize changes in expression of ovarian activins, inhibins, follistatin and activin receptors during reproductive cyclicity. Specific Aim 3: To determine if relative changes in activins, inhibins, and (or) follistatin alter granulosa cell function. Proposed studies should provide insight into the control of follicular selection and growth. A greater understanding of mechanisms which regulate follicular development and selection of dominant follicles may be beneficial in identifying fundamental causes of aberrant ant follicular development in women. For example, in polycystic ovary syndrome (PCOS), selection of a dominant preovulatory follicle occurs infrequently, thereby leading to accumulation of many cystic follicles in the ovary and chronic anovulation. Knowledge gained in the proposed studies should increase our understanding of the roles of activins, inhibins, and follistatin in normal follicular development. A better understanding of normal physiology, in turn, will increase our ability to understand pathophysiological conditions such as PCOS.